Campylobacter is a major human pathogen that infects an estimated 2.5 million people each year resulting in an estimated $1.9 billion economic loss in the U.S. Campylobacter jejuni is a common human enteric pathogen that causes acute enterocolitis and increases the risk of developing long-term intestinal dysfunction such as post- infectious irritable bowel syndrome. The innate immune mechanisms responsible for intestinal pathology in C. jejuni-induced colitis are still poorly understood. Innate lymphoid cells (ILCs) are a heterogeneous family of novel regulators of both protective and pathogenic responses in the gut. However, the cellular and molecular mechanisms of protective versus pathogenic responses mediated by distinct populations of ILCs are scantily understood. This gap of knowledge severely limits the development of novel therapies to treat the disease. Therefore, a deeper understanding of the role of ILCs in the pathogenesis of infectious colitis and associated sequelae is needed to develop better therapeutic approaches that control intestinal inflammation and protection against mucosal pathogens. Our exciting preliminary data strongly suggest that a unique population of IFN?- producing ILCs that lack natural cytotoxicity receptors (NCR) promotes colitis in a mouse model of C. jejuni infection. Intriguingly, we revealed that the transcription factor ROR?t plays a critical role in the development and/or maintenance of these NCR-ILC1s. The overall objective of this proposal is to understand the role of these ILCs in promoting infectious colitis. Our working model is that during the course of C. jejuni infection, ILC3s undergo conversion to a unique population of IFN?-producing NCR-ILC1s, which promotes intestinal pathology. To test this hypothesis, we propose three specific aims. In Aim 1, we will determine the developmental origin of pathogenic IFN?-producing NCR-ILC1s using a genetic cell fate-mapping approach. In Aim 2, we will determine the colitogenic potential of NCR-ILC1s using an adoptive cell transfer approach. In Aim 3, we will determine the relevance of these NCR-ILC1s to human disease in mice with a reconstituted human immune system. Completion of these aims will lead to a better understanding of the ILC-dependent mechanisms that control intestinal inflammation. The research proposed is significant because it will address a critical gap in our understanding of the role of ILCs in promoting intestinal inflammation. Together, this knowledge will guide future efforts to identify targets to rationally design therapeutic strategies that limit intestinal inflammation. These studies will also generate new knowledge in basic ILC biology in a tractable murine model of a major bacterial pathogen.